ProjectSummary Thisproposalisafour-yearplanforaMentoredResearchScientistDevelopmentAward(K01),thegoalof whichistofacilitatethecareertransitionofXuanmao(Mao)Chenfromajuniorinvestigatorintofullresearch independence.ThisK01awardconsistsofaprogramdesignedtosupporthiscareerdevelopmentduringthis criticalperiodbyprovidingtraininginneurobiologyofaging,proteomicsandIlluminasequencingwhile enhancinghisexpertiseinthefieldofprimarycilia.TheprimarymentorwillbeRickCote,whoisawell- establishedscientiststudyingphosphodiesteraseinspecializedciliaofphotoreceptors.Chenwillalsobeco- mentoredbyDanielStorm,whoisawell-knownexpertinthefieldofadenylylcyclaseandcognition;?George Martin,whoisaprominentscientistinAlzheimer?sdisease;?andDavidClapham,whoisanoutstandingexpert ofprimarycilia.Thetrainingplanincludesstructuredmentorshipwithanadvisorycommittee,agrantwriting program,teachingworkshops,participationinresearchseminarsandtrainingcourses,andone-on-one mentorshipforteachingandresearch.TheresearchplanwillstudytheroleofcAMPsignalinginprimarycilia inhippocampaladultneurogenesisandbrainaging.Primaryciliaplayacriticalroleindevelopmentandtissue regeneration,butlittleisknownabouttheircontributionstobrainaging.Geneticevidencefromhumanpatients supportstheassociationbetweendefectsinprimaryciliaandcognitiveimpairmentandneurodegeneration. Chenwillfocushisstudyontype3adenylylcyclase(AC3),amajoradenylylcyclasecriticalforcAMPsignaling inneuronalcilia.Previously,ChenfoundthatAC3conventionalknockoutmiceexhibitage-relatedpleiotropic phenotypesincludingneuronalatrophy,synapticdysfunction,olfactorydeficit,memorydeficitsandalterationof sleeparchitecture.Chen,incollaborationwithRichardPalmiter,hasrecentlygeneratedanAC3floxedmouse strainthatwillbeusedtoablateAC3inatissue-andtime-dependentmanner.ChenhypothesizesthatcAMP signalingintheprimaryciliaofcentralneuronsissimilartothatinolfactorysensorycilia,andthatperturbations incAMPsignalinginneuronalprimaryciliainfluenceadultneurogenesisandbrainaging.Hewillfirstdevelop methodstomanipulatecAMPgenerationinprimaryciliatofacilitatethestudyofcAMPsignalinginprimary cilia,andthenidentifymolecularcomponentsthatmediatethecAMPsignaltransductionpathwayinneuronal primarycilia.HewillfurtherdeterminetheroleofAC3inneuronalprimaryciliainhippocampaladult neurogenesisandexamineiflossofAC3inadult-bornhippocampalneuronsleadstocognitivedeficits. Alternatively,hewillexaminethepotentialroleofAC3instresshormoneregulationandexamineifthereare age-associatedstructuralchangeswithneuronalprimarycilia.Together,completionofthisworkwillprovide foundationforChentodevelopastrongresearchprogramtorevealthefunctionofciliarycAMPsignalingand studythecontributionsofimpairedcAMPsignalinginneuronalprimaryciliatobrainaging.